title: Posterior microphthalmia and nanophthalmia in Tunisia caused by a founder c.1059_1066insC mutation of the PRSS56 gene.
abstract: Congenital microphthalmia (CMIC) is a common developmental ocular disorder characterized by a small, and sometimes malformed, eye. Posterior microphthalmia (PM) and nanophthalmia are two rare subtypes of isolated CMIC characterized by extreme hyperopia due to short axial length and elevated lens/eye volume ratio. While nanophthalmia is associated with a reduced size in both anterior and posterior segments, PM involves a normal-size anterior chamber but a small posterior segment. Several genes encoding transcription and non-transcription regulators have been identified in different forms of CMIC. MFRP gene mutations have, for instance, been associated with nanophthalmia, and mutations in the recently identified PRSS56 gene have been linked to PM. So far, these two forms of CMIC have been associated with 9 mutations in PRSS56. Of particular interest, a c.1059_1066insC mutation has recently been reported in four Tunisian families with isolated PM and one Tunisian family with nanophthalmia. Here, we performed a genome-wide scan using a high density single nucleotide polymorphism (SNP) array 50 K in a large consanguineous Tunisian family (PM7) affected with PM and identified the same causative disease mutation. A total of 24 polymorphic markers spanning the PRSS56 gene in 6 families originating from different regions of Tunisia were analyzed to investigate the origin of the c.1059_1066insC mutation and to determine whether it arose in a common ancestor. A highly significant disease-associated haplotype, spanning across the 146 kb of the 2q37.1 chromosome, was conserved in those families, suggesting that c.1059_1066insC arose from a common founder. The age of the mutation in this haplotype was estimated to be around 1,850 years. The identification of such 'founder effects' may greatly simplify diagnostic genetic screening and lead to better prognostic counseling.
authors.affiliation: Laboratoire de microorganismes et biomolécules, Centre de Biotechnologie de Sfax, Tunisia. maryam_bensaid@yahoo.fr
authors.forename: Mariem Ben
authors.initials: MB
authors.lastname: Said
authors.forename: Ebtissem
authors.initials: E
authors.lastname: Chouchène
authors.forename: Salma Ben
authors.initials: SB
authors.lastname: Salem
authors.forename: Kods
authors.initials: K
authors.lastname: Daoud
authors.forename: Leila
authors.initials: L
authors.lastname: Largueche
authors.forename: Walid
authors.initials: W
authors.lastname: Bouassida
authors.forename: Zeineb
authors.initials: Z
authors.lastname: Benzina
authors.forename: Hammadi
authors.initials: H
authors.lastname: Ayadi
authors.forename: Peter
authors.initials: P
authors.lastname: Söderkvist
authors.forename: Leila
authors.initials: L
authors.lastname: Matri
authors.forename: Mounira
authors.initials: M
authors.lastname: Hmani-Aifa
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D003241:Consanguinity; D005260:Female; D018703:Founder Effect; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008297:Male; D008850:Microphthalmos / Q000201:enzymology / Q000235:genetics*; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D057057:Serine Proteases / Q000235:genetics*; D014416:Tunisia
chemical_list: C558176:PRSS56 protein, human; D057057:Serine Proteases
keywords: A; CMIC; DNA; Founder effect; MFRP; Microarray; Microphthalmia; Nanophthalmia; PCR; PM; PRSS56; Polymerase Chain Reaction; SNP; Tunisia; anophthalmia; base pair; bp; congenital microphthalmia; deoxyribonucleic acid; h; hour; kb; kilobase; membrane frizzled-related protein; nanogram; ng; posterior Microphthalmia; serine protease 56; single nucleotide polymorphism